High-fat diets (HFDs) promote hyperphagia and adiposity in animals and human beings. To test the hypothesis that limitations on fat oxidation underlie this propensity for diet-induced obesity, rats were treated with fenofibrate, which enhances fat oxidation mainly in liver by inducing expression of enzymes and proliferation of organelles involved in fatty acid oxidation. Male Sprague-Dawley rats were fed a HFD (42% fat calorie) for 2 weeks. Rats ranked in the top and bottom thirds for weight gain during this feeding period were designated as obesity prone (OP) and obesity resistant (OR), respectively. Fenofibrate was added to the HFD (0.025% wt/wt) for half of the OP and OR rats. During the next 10 days, fenofibrate treatment significantly (P<.05) reduced food intake, weight gain, feed efficiency, and adiposity in OP rats to levels seen in control OR rats, but had no such effects in OR rats. Fenofibrate treatment increased whole-body fatty acid oxidation, and in liver, the expression of carnitine palmitoyl transferase I only in OP rats, but enhanced expression of acyl-CoA oxidase in both OP and OR rats. Restricting food intake of OP rats to levels seen in rats given fenofibrate similarly reduced weight gain but had little effect on weight of fat pads. Treatment with the daily dosage of fenofibrate given as a bolus did not produce a conditioned flavor aversion. These results suggest that enhancement of mitochondrial fatty acid oxidation in liver may be an effective phenotype-based treatment strategy for dietary obesity.